Most elapid snakes produce venoms that contain alpha-neurotoxins (α-NTXs), which are proteins that cause post-synaptic blockade and paralysis in snakebite envenoming. However, existing elapid antivenoms are known for their low potency in neutralizing the neurotoxic activity of α-NTXs, while the immunological basis has not been elucidated. In this study, a structure-based major histocompatibility complex II (MHCII) epitope predictor of horse (), complemented with DM-editing determinant screening algorithm was adopted to assess the immunogenicity of α-NTXs in the venoms of major Asiatic elapids (). The scoring metric MR, representing the relative immunogenic performance of respective α-NTXs, showed all α-NTXs have an overall low MR of <0.3, and most of the predicted binders feature non-optimal P1 anchor residues. The MR scores correlate strongly (R = 0.82) with the potency scores (p-score) generated based on the relative abundances of α-NTXs and the neutralization potency of commercial antivenoms. The immunoinformatic analysis indicates that the inferior antigenicity of α-NTXs is not only due to their small molecular size but also the subpar immunogenicity affected by their amino acid composition. Structural modification with conjugation and synthetic epitope as immunogen may potentially enhance the immunogenicity for improved antivenom potency against α-NTXs of elapid snakes.